Fat and sugar flavor preference and acceptance in C57BL/6J and 129 mice: experience attenuates strain differences

C57BL/6J (B6) mice display stronger preference and acceptance for various sweeteners than do 129 mice (129P3/J, 129X1/SvJ). The present experiment compared the preference of these strains for fat flavor as well as sweet taste using 24-h two-bottle preference tests. Fat flavor preference was evaluated using non-nutritive (olestra) and nutritive (Intralipid) oil emulsions. In initial oil vs. water tests olestra preference and intake were greater in B6 mice than 129 mice. Similar strain differences were obtained with low (0.313%-5%) but not high (10%-20%) Intralipid concentrations. When retested with Intralipid the B6 and 129 mice showed strong (>90%) preferences for the nutritive oil although B6 mice still consumed more oil at low concentrations. A second olestra test revealed increased oil preference and acceptance in B6 and 129X1/SvJ mice while 129P3/J mice still did not prefer olestra to water. Sweetener tests revealed stronger saccharin and sucrose preferences in B6 mice than in 129 mice. These strain differences in sweetener preference disappeared when the mice were retested with sucrose and saccharin. However, B6 mice continued to consume more saccharin and sucrose (at low concentrations) than did 129 mice. The profile of strain differences for non-nutritive and nutritive oils was similar to those observed for non-nutritive and nutritive sweeteners. The differential sweetener preferences of B6 and 129 mice is explained by differences in their sweet taste receptors but why the strains also differ in their initial fat flavor preference is not clear. The experientially-induced increases in oil and sweetener preferences displayed by the mice are attributed to the post-oral actions of Intralipid and sucrose. These findings along with intragastric infusion data suggest that B6 and 129 mice differ in their oral but not their post-oral response to fat and sugar.     

Enhanced sucrose and Polycose preference in sweet "sensitive" (C57BL/6J) and "subsensitive" (129P3/J) mice after experience with these saccharides

Prior research with inbred mouse strains indicates that C57BL/6J (B6) mice display stronger preference and acceptance for various sweeteners than do 129P3/J (129) mice. Experiment 1 examined the extent to which this strain difference could be modified by repeated exposure to sucrose. Sucrose-naive 129 mice displayed weaker preferences than did B6 mice for 0.5% to 4% sucrose solutions during 23h/day sugar vs. water tests. Sucrose preference did not differ at 8-32% concentrations. Yet, when retested with sucrose, the 129 and B6 mice showed identical robust preferences (>90%) for 0.5-32% solutions. The strains also did not differ in sucrose preference in tests with descending sucrose concentrations (0.5-0.0625%). Sucrose-experienced 129 mice also showed enhanced preference for dilute saccharin solutions suggesting that their sweet taste responsivity was enhanced. Experiment 2 revealed that preference for dilute saccharin solutions was enhanced by prior saccharin experience in B6 but not 129 mice. Experiment 3 tested the strains with Polycose which has a palatable taste different from that of sucrose. Polycose-naive 129 mice displayed weaker preferences for dilute (0.5-4%) but not concentrated (8-32%) Polycose solutions relative to B6 mice. In the second test series Polycose preferences were nearly identical in the two strains. In Experiments 1 and 3, prior sucrose or Polycose experience also reduced or eliminated strain differences in saccharide acceptance (absolute intake) at higher but not lower concentrations. Thus, exposure to the oral and post-oral actions of sucrose and Polycose increased saccharide preference in B6 mice and even more in 129 mice so that the strain difference virtually disappeared. Whether the 129 mice responded to the taste or other properties (e.g., odor) of the dilute saccharide solutions is not certain but their gustatory sensitivity needs to be reconsidered.     

Oral, post-oral and genetic interactions in sweet appetite

Inbred mouse strains differ in their preferences for sweeteners, due in part to variations in their T1R3 sweet taste receptor. Recent studies of sweet sensitive C57BL/6J (B6) and subsensitive 129P3/J (129) mice indicate that experiential and post-oral effects of sugar substantially modify sweetener preference. In fact, the strain difference in sucrose preference disappeared after the mice were given 23 h/day tests with sucrose at ascending concentrations (0.5-32%). Intragastric infusions of sucrose (16%) also conditioned increased preference for and absolute intake of flavored sweet solutions in B6 and 129 mice. An operant analysis of sweetener appetite revealed, unexpectedly, that sugar-experienced 129 mice respond more vigorously than B6 mice for 16% sucrose rewards. These findings indicate that experiential and nutritional factors can, to some degree, override genetic differences in peripheral taste sensitivity in determining food appetite.     

Sucrose motivation in sweet "sensitive" (C57BL/6J) and "subsensitive" (129P3/J) mice measured by progressive ratio licking

As compared to C57BL/6J mice, 129P3/J mice show weaker preferences for and lower intakes of dilute sugar solutions. These differences have been attributed to genetic differences in their sweet taste receptor. The two mouse strains do not differ, however, in their intake of concentrated sugar solutions. The post-oral satiating effect of concentrated sugar solutions may mask strain differences in the avidity for these solutions. This hypothesis was investigated using fixed ratio (FR, low demand) and progressive ratio (PR, high demand) operant licking tests (22h/day) to measure sugar appetite. In Experiment 1, sucrose-experienced 129 mice licked less than did B6 mice for 4% but not for 16% sucrose in free access bottle tests and FR operant tests. Yet, in PR tests the 129 mice licked as much for 4% sucrose and more for 16% sucrose than did B6 mice. In Experiment 2, sucrose-naive 129 mice licked less than did B6 mice in FR and PR tests with 0.4% saccharin but the strains did not differ in PR licking in their first test with 16% sucrose. After they were given unconstrained bottle access to 16% sucrose for 3 days, the 129 mice now licked more than B6 mice in a second sucrose PR test. Thus, despite having a less sensitive sweet taste receptor, 129 mice are as much or more motivated to obtain sucrose than are B6 mice and appear to be more influenced by prior experience with sugar. This suggests that the strains differ in their central reward processing of sweet taste.     

Behavioural differences between C57BL/6 and 129S6/SvEv strains are reinforced by environmental enrichment

Housing in enriched environment has been advocated as a means for controlled variation of environmental conditions in transgenic studies to explore interactions between genes and surroundings. In the present study, behavioural phenotypes of C57Bl/6 (B6) and 129S6/SvEv (129) mice, housed in either standard laboratory conditions or environmentally enriched conditions, were explored. Housing in enriched conditions increased exploratory activity in the plus-maze and reduced habituation in the locomotor activity test in B6 mice, whereas in 129 mice increased hot plate latencies and reduced aggression were observed. Compared to B6, 129 strain displayed lower exploratory activity in the plus-maze and locomotor activity test, longer hot plate latencies, spent more time immobile in the forced swim test and engaged more in social interaction. These behavioural differences between the two strains were reproducible independent of pre-experimental housing conditions. Moreover, environmental enrichment accentuated dissimilarities between the strains in the plus-maze, locomotor activity, hot plate and forced swim test. By contrast, strain differences in anxiety-like behaviours in the plus-maze test and in aggressive encounters in the resident-intruder test were not reproducible in mice housed in alternative environmental conditions, suggesting a strong contribution of environmental factors to the development of these phenotypes. It is concluded that the application of environmental enrichment in addition to standard housing conditions is a meaningful approach for testing reproducibility of behavioural findings within one laboratory.     

Voluntary Sodium Chloride Consumption by Mice: Differences Among Five Inbred Strains

We examined voluntary NaCl intakes of five mouse strains: NZB/B1NJ, SM/J, 129/J, C57BL/6ByJ, and CBA/J. Using two-bottle tests with water as one choice, the mice were offered series of progressively increasing or progressively decreasing NaCl concentrations (37.5–600 mMNaCl in 48-h tests), then 300 mMNaCl for 6 days and 75 mMNaCl for 8 days. Low concentrations of NaCl were more avidly accepted by mice given the increasing rather than the decreasing series. However, irrespective of the test order, test duration, or how the results were expressed (i.e., as raw intakes, intakes corrected for body weights, or preferences), the NZB/B1NJ mice always had higher NaCl acceptance than did the CBA/J mice. The SM/J, 129/J, and C57BL/6ByJ strains were intermediate between the NZB/B1NJ and the CBA/J strains, but their distributions varied from concentration to concentration. Low (150 mM) NaCl concentrations were avoided by the C57BL/6ByJ and CBA/J mice, but the NZB/B1NJ, SM/J and 129/J mice either preferred or were indifferent to them. High (300 mM) NaCl concentrations were strongly avoided by all mice, except for the NZB/B1NJ strain. It is suggested that separate genes underlie the strain differences in acceptance of dilute and concentrated NaCl solutions.     

Taste perception of monosodium glutamate and inosine monophosphate by129P3/J and C57BL/6ByJ mice

Our previous studies have shown that in long-term two-bottle preference tests, mice from the C57BL/6ByJ (B6) inbred strain drink more monosodium glutamate (MSG) and inosine monophosphate (IMP) than mice from the 129P3/J (129) inbred strain. The goal of this study was to examine whether this variation in consumption could be attributed to strain differences in perception of the taste quality of MSG and IMP. We developed a conditioned taste aversion (CTA) in B6 and 129 mice to 100 mM MSG or 10 mM IMP and used a brief-access taste assay to examine CTA generalization. B6 and 129 mice did not differ in the generalization patterns following CTA to MSG: mice from both strains generalized CTA from MSG to NaCl. In contrast, strain differences in the generalization patterns were evident following the CTA to IMP: while mice from both strains generalized CTA from IMP to MSG, 129 mice tended to have stronger CTA generalization to saccharin and d-tryptophan, both of which are perceived as sweet by humans. These data suggest that the strain differences in MSG consumption are not due to variation in perception of the taste quality of MSG. Instead, the differential intake of IMP likely reflects strain differences in the way the taste quality of IMP is perceived. Our data suggest that mice perceive MSG and IMP as complex taste stimuli: some taste components are shared between these two substances, but their relative intensity seems to be different for MSG and IMP. The amiloride-sensitive salt taste component is more prevalent in MSG than in IMP taste, and in B6 compared with 129 mice.     

Amino acid and carbohydrate preferences in C57BL/6ByJ and 129P3/J mice

Compared with mice from the 129P3/J (129) inbred strain, mice from the C57BL/6ByJ (B6) inbred strain have higher consumption of several sweet-tasting amino acids and carbohydrates. To examine the relative contribution of taste and nutritive properties in these strain differences, we measured responses of B6 and 129 mice to eight sweet and non-sweet amino acids and carbohydrates in two-bottle preference tests with water. Mice from the two strains did not differ in consumption of non-sweet l-valine and l-histidine. Compared with 129 mice, B6 mice had higher consumption and lower preference thresholds for sweet amino acids l-glutamine, l-alanine and l-threonine, monosaccharides glucose and fructose, and maltooligosaccharide. These data suggest that differences in gustatory responsiveness are an important factor underlying higher consumption of some amino acids and carbohydrates by B6 mice compared with 129 mice. It is likely that in B6 mice, higher sweet taste responsiveness results in increased consumption of sweet-tasting amino acids and sugars, and higher taste responsiveness to complex carbohydrates results in increased consumption of maltooligosaccharide. However, postingestive processes also influence nutrient consumption and may be responsible for higher intake of carbohydrates compared with sweet-tasting amino acids. Results of this study set the stage for genetic analysis of differences between B6 and 129 mice in taste responsiveness and macronutrient consumption.     

Telemetric recording of sleep and home cage activity in mice

STUDY OBJECTIVES: This study assessed differences in spontaneous sleep and locomotor activity in inbred and hybrid mouse strains and evaluated telemetry for recording sleep in mice. DESIGN: Uninterrupted recordings of sleep and home cage activity were obtained in four mouse strains. Pre-operative and post-operative home cage activity was obtained in two strains. SETTINGS: N/A PARTICIPANTS: The subjects were mice of three inbred (C57BL/6J (B6), n=25; BALB/cJ (C), n=24; DBA/2J (D2), n=30) strains and one hybrid (CB6F1/J (CB6: C x B6), n=19) strain. INTERVENTIONS: Electroencephalogram (EEG) and activity were recorded by telemetry, and behavioral states were visually scored based on EEG and activity records. Home cage activity was determined utilizing photobeam interruptions. MEASUREMENTS AND RESULTS: 1) Among the three inbred strains: C mice had the least sleep and the greatest amount of activity; D2 mice exhibited the least non-rapid-eye-movement (NREM) sleep, the longest average NREM-bout length, and the greatest diurnal ratio of sleep and were the most inactive; B6 mice had the most sleep and an intermediate activity level; no differences among inbred strains were observed in total REM. The CB6 mice exhibited intermediate levels of total sleep and activity and had greater amounts of REM compared to its parental strains. 2) Total operative mortality was 9.3%, with all deaths occurring within 3 to 9 days after the operation; significant reductions in activity were observed after the operation. CONCLUSION: Differences in spontaneous sleep and activity exist among inbred and hybrid mouse strains. Accurate determination of sleep states in mice can be achieved with telemetrically recorded EEG and activity.     

Nutrient preference and diet-induced adiposity in C57BL/6ByJ and 129P3/J mice

Purified carbohydrates and fats are usually palatable to humans and other animals, and their consumption often induces weight gain and accumulation of fat. In this study, we examined consumption of complex carbohydrates (cornstarch and Polycose) and fats (soybean oil and margarine) in mice from two inbred strains, C57BL/6ByJ and 129P3/J. At lower concentrations of liquid nutrients tested using two-bottle tests, when the amounts consumed had negligible energy content, the C57BL/6ByJ mice had higher acceptance of Polycose and soybean oil. This was probably due to strain differences in chemosensory perception of Polycose and oil. At higher concentrations, the mice consumed a substantial part of their daily energy from the macronutrient sources, however, there were no or only small strain differences in nutrient consumption. These small differences were probably due to strain variation in body size. The two strains also did not differ in chow intake. Despite similar energy intakes, access to the nutrients resulted in greater body weight (BW) gain in the C57BL/6ByJ mice than in the 129P3/J mice. The diet-induced weight gain was examined in detail in groups of 2-month-old C57BL/6ByJ and 129P3/J mice given ether chow, or chow and margarine to eat. Access to margarine did not increase total energy consumption of either strain. It increased BW and adiposity of the C57BL/6ByJ mice, but only after they reached the age of approximately 3 months. There were no differences in BW and adiposity between control and margarine-exposed 129P3/J mice. The results suggest that diet-induced adiposity in the B6 mice depends on age and does not depend on hyperphagia.     

Strain Differences in Rewarded Discrimination Learning Using the Olfactory Tubing Maze

We trained BALB/c Byllco (C), CD-1, SV 129/SvPasCr1 (129 SV), C57BL/6 (B6) and DBA/2J (D2) mice using the olfactory tubing maze with the hope of gaining insight into behavioral genetics related to learning and memory processes. All strains of mice acquired the odor–reward associations using this new task except the D2 strain. The C, CD-1, and 129 SV consistently remembered the associations from the sixth 20-trial training session, reaching 80% ± 5 correct responses in session seven. The B6 mice required one more session to reach 76%, while the D2 mice never learned the correct odor–reward associations. All mice learned the paradigm and the timing of the task, although the 129 SV mice decreased slower the inter-trial intervals across sessions. With this new task, D2 mice, with a deficit totally devoted to an impairment on learning and memory, can be used as a model of hippocampal dysfunction, in some respects like that observed in human amnesic patients whose selective hippocampal-dependent memory is deeply impaired. The high-scoring strains (C, CD-1, and 129 SV) seem to be ideal in this task to study a gene-targeting mutation postulated to reduce behavioral performance, and inversely, for D2 mice. The moderate-scoring strain, B6, should be ideal for allowing gene-targeting to go either way. In addition, this new task, which enables automated training of odor associations, could be used for studying the phenomenon of transitivity in mice, as described in rats.Edited by Stephen Maxson     

Heroin-induced locomotor activity and conditioned place preference in C57BL/6J and 129P3/J mice

Differences in the locomotor stimulating and rewarding properties of drugs of abuse have been described in several inbred strains of mice, and comparisons of inbred strains with differing responses to drugs of abuse may provide crucial insight into the question of individual vulnerability to the effects of drugs of abuse. The present study was designed to examine the rewarding and locomotor-stimulating effects of heroin in C57BL/6J and 129P3/J mice. Heroin produced a robust dose-dependent locomotor stimulation in both strains. Both strains also developed conditioned place preference to heroin, again in a dose-dependent manner. However C57BL/6J mice developed conditioned place preference to only the two lowest doses of heroin tested, while the 129P3/J counterparts showed conditioned place preference to only the three highest doses tested. These studies indicate that 129P3/J mice are less sensitive to the rewarding effects of heroin than are age-matched C57BL/6J mice.     

Air and shock two-way shuttlebox avoidance in C57BL/6J and 129X1/SvJ mice

Despite multiple advantages of the use of electric shock as an aversive stimulus, reasons exist for considering alternative aversive stimuli. In the present study, we examined and compared the acquisition of two-way shuttlebox avoidance with 275.8-kPa (40-psi) pulsed air and continuous 0.4-mA shock in two strains of mice commonly employed in targeted gene mutation research, C57BL/6J and 129X1/SvJ. Each trial consisted of a 5-s warning stimulus (WS, light) during which shuttling to the other side cancelled delivery of the aversive stimulus. Once initiated, the aversive stimulus remained active for 20 s or until an escape response occurred. For C57BL/6J mice, air and shock were equally and highly effective aversive stimuli. In contrast, air was less effective than shock for 129X1/SvJ mice. C57BL/6J mice outperformed 129X1/SvJ mice for both stimulus types. For 129X1/SvJ mice, longer escape latencies were observed initially for air, suggesting that shock is more effective. However, these differences in latency dissipated within the first seven sessions. Nevertheless, by the end of the 17-day study, asymptotic levels of avoidance proficiency were substantially lower for air than for shock in 129X1/SvJ mice. These results indicate that air is a suitable substitute for shock as an aversive stimulus in shuttlebox active avoidance; however, the relative efficacies of these aversive stimuli appear to depend upon the strain chosen for study.     

Cat odor exposure induces distinct changes in the exploratory behavior and Wfs1 gene expression in C57Bl/6 and 129Sv mice

129Sv and C57Bl/6 (Bl6) strains are two most widely used inbred mice strains for generation of transgenic animals. The present study confirms the existence of substantial differences in the behavior of these two mice strains. The exploratory behavior of Bl6 mice in a novel environment was significantly higher compared to 129Sv mice. The exposure of mice to cat odor-induced an anxiety-like state in Bl6, but not in 129Sv mice. The levels of Wfs1 gene expression did not differ in the prefrontal cortex, mesolimbic area and temporal lobe of experimentally naive Bl6 and 129Sv mice. However, after cat odor exposure the expression of Wfs1 gene was significantly lower in the mesolimbic area and temporal lobe of Bl6 mice compared to 129Sv strain. Dynamics of Wfs1 gene expression and exploratory behavior suggest that the down-regulation of Wfs1 gene in Bl6 mice might be related to the increased anxiety. Further studies are needed to test the robustness and possible causal relationship of this finding.     

Evaluation of exploration and risk assessment in pre-weaning mice using the novel cage test

Exploration and risk behaviour (risk assessment/risk taking) are critical to enable mice to cope with novel situations and gain control over their environment. Evaluation of those behaviours would therefore be a useful part of early phenotypic characterization of genetically modified mice, allowing early detection of behavioural phenotypes that require special attention and/or are of scientific interest. This study aimed to evaluate exploration and risk behaviour in pre-weaning mice using the novel cage test, which consists in exploration of a novel, clean, Makrolon type III cage. The results of this test were compared with those obtained in more complex and established tests to which the same mice were subjected as adolescents and young adults. Mice of two inbred strains (129S6/Bkl, n=10; C57BL/6Bkl, n=10) and one hybrid (B6CBAF1/Bkl, n=10) were used for validation of the test. The animals were tested in the novel cage (at weaning), the open field test (at 5 weeks), and from 9 weeks of age in three other tests: the elevated plus-maze, the concentric square field and the rat exposure test. The novel cage test effectively detected strain differences in pre-weaning mice as regards exploration and risk behaviour and the results were largely consistent with those obtained in the established tests later in life. In all tests 129S6 displayed a low locomotion and high risk assessment, while C57BL/6 and B6CBAF1 showed high locomotion and exploration. In addition high levels of risk taking were observed in C57BL/6. The novel cage test is rapid, requires no special equipment and is as discriminatory as more complex tests in detecting strain/genotype differences. This suggests that the novel cage test is a valuable tool for evaluation of exploration, risk assessment and risk taking in juvenile mice.     

Loss of Aggression, After Transfer onto a C57BL/6J Background, in Mice Carrying a Targeted Disruption of the Neuronal Nitric Oxide Synthase Gene

Phenotypic differences among mice with disrupted genes and those with wild-type alleles have not provided the necessary evidence for desired gene/phenotype correlations. These differences could be due to "passenger genes" from the donor 129 strains that are used to produce stem cells. Three variations of attack behavior were measured, using mice carrying a disruption of the neural nitric oxide synthase gene. In the first population, the disrupted gene had been maintained on a mixed background including C57BL/6J and 129 alleles. We have developed a second population in which the disrupted gene was transferred onto a C57BL/6J background during five backcross generations. On the mixed C57BL/6J-129 background, mice homozygous for disrupted Nos1 alleles attacked more frequently, had shorter attack latencies, and presented a greater number of attacks than mice carrying nondisrupted alleles. On the C57BL/6J background, no significant difference persisted between the carriers of the disrupted gene and their noncarrier siblings. The noncarriers on the mixed C57BL/6J-129 background, and the carriers or noncarriers on the C57BL/6J background, did not differ from C57BL/6J. The frequency of attacking males was identical in the homozygous carriers of the disrupted gene, in the mixed C57BL/6J-129 background, and in the 129/SvPas, which approximates the 129/SvJae strain from which the stem cells were derived to produce the disrupted Nos1 gene. These results suggest that Nos1 disruption was not implicated in attack behavior. A possible passenger-gene effect from the 129 donor strain is discussed.     

Differential effects of two types of environmental novelty on activity and sleep in BALB/cJ and C57BL/6J mice

Change in the sleeping environment can produce significant alterations in sleep. To determine how these alterations may vary with the amount of change and the relative reactivity of the sleeper, we examined the influences of environmental novelty on sleep in two mouse strains that differ in behavioral anxiety. Mice [BALB/cJ (n=7) and C57BL/6J (n=8)] were implanted for recording EEG and activity via telemetry. Following baseline data collection, activity and sleep were examined over 46 h after routine cage change, after placing a simple novel object (PVC Tee) in the home cage, and after handling controls. Mice of both strains showed immediate increases in activity and decreases in rapid eye movement sleep (REM) and non-REM (NREM) after cage change and novel object. Within strain, changes in activity and sleep were greater after cage change than after novel object. Changes in activity and sleep time were significantly correlated in each strain. Compared to C57BL/6J mice, BALB/cJ mice exhibited greater and longer duration initial reductions in sleep time, and greater increases in EEG slow wave activity power after cage change and novel object, but these changes were not followed with subsequent increases in sleep time. In contrast, C57BL/6J mice showed significantly greater subsequent increases in sleep time following the initial reductions induced by both manipulations. The results suggest that initial decreases and subsequent increases in sleep time are related to putative differences in the intensity of environmental novelty (cage change>novel object) and to previously described strain differences in anxiety (BALB/cJ>C57BL/6J).     

Antibody class switching differs among SJL, C57BL/6 and 129 mice

Inbred mouse strains used for gene manipulation studies vary in many respects, including immune system function. These differences can interfere with data interpretation unless the mice are well backcrossed. Here, we show that antibody class switching to IgG3 in cultured splenic B cells from Swiss James Lambert (SJL) and 129/Sv mice is 2- to 6-fold less efficient compared with C57BL/6 (B6). Under optimal stimulation conditions, IgA switching is also 2- to 19-fold lower in SJL and 129/Sv B cells. Splenic B cells from SJL mice express higher levels of CD19 and CD21 compared with B6, and their CD21(high)CD23(low) B cells have little CD9 expression, suggesting atypical marginal zone (MZ) B cells. However, sort purification of splenic B cell subsets did not equalize in vitro class switching to IgG3 or IgA between SJL and B6. 129/Sv spleens have a 3-fold greater number of MZ B cells compared with B6, with similar CD9 expression. Poor IgG3 switching by 129/Sv B cells is specific to CD23(high) follicular B cells, whereas similar changes in IgA switching are seen in both CD21(high) and CD23(high) B cell subsets from 129/Sv. Therefore, the functions and phenotypes of mature B cells differ among three common strains of mice.     

Identification of chromosome intervals from 129 and C57BL/6 mouse strains linked to the development of systemic lupus erythematosus

Systemic lupus erythematosus is an autoimmune disease in which complex interactions between genes and environmental factors determine the disease phenotype. We have shown that genes from the non-autoimmune strains 129 and C57BL/6 (B6), commonly used for generating gene-targeted animals, can induce a lupus-like disease. Here, we conducted a genome-wide scan analysis of a cohort of (129 x B6)F2 C1q-deficient mice to identify loci outside the C1qa locus contributing to the autoimmune phenotype described in these mice. The results were then confirmed in a larger dataset obtained by combining the data from the C1q-deficient mice with data from previously reported wild-type mice. Both analyses showed that a 129-derived interval on distal chromosome 1 is strongly linked to autoantibody production. The B6 genome contributed to anti-nuclear autoantibody production with an interval on chromosome 3. Two regions were linked to glomerulonephritis: a 129 interval on proximal chromosome 7 and a B6 interval on chromosome 13. These findings demonstrate that interacting loci between 129 and B6 mice can cause the expression of an autoimmune phenotype in gene-targeted animals in the absence of any disrupted gene. They also indicate that some susceptibility genes can be inherited from the genome of non-autoimmune parental strains.